Tri-substituted (aryl or heteroaryl) derivatives and pharmaceutical compositions containing the same

A compound selected from the group consisting of:

• (.+-.)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2-furyl)ethyl]pyridine;
• (.+-.)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2-thienyl)ethyl]pyridine;
• (.+-.)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]-3-methylimida zole;
• (.+-.)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine;
• (.+-.)-4-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]pyridine;
• (.+-.)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4fluorophenyl)ethyl]pyrid ine;
• (.+-.)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4trifluoromethylphenyl)et hyl]-pyridine;
• (.+-.)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2-methoxyphenylethyl)]pyr idine;
• (.+-.)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-methoxyphenyl)ethyl]pyr idine;
• (.+-.)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-methylphenyl)ethyl]pyri dine;
• (.+-.)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-(3-methylphenyl)ethyl]pyri dine;
• (.+-.)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-(3-cyclopentyloxy-4-methox yphenyl)ethyl]pyridine;
• (.+-.)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]-3,5-dichlorop yridine;
• (.+-.)-2-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine;
• (.+-.)-4-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]aniline;
• (.+-.)-4-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]benzoic acid;
• (.+-.) Ethyl N-[4-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]phenyl]carba mate;
• (.+-.)-N-(4-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]phenyl )-N'-ethylurea;
• (.+-.)-N-(4-[1-(3-cyclopentyloxy-4-methoxyphenyl)]-2-(4-pyridyl)ethyl)pheny l]acetamide;
• (.+-.)-3-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine;
• (.+-.)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyrimidine;
• (.+-.) -4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-hydroxymethylphenyl)ethyl]py ridine;
• (.+-.)-4-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]benzamide
• (.+-.) Ethyl-4-[1-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(4-phenylethyl]benzoate;
• and
• (.+-.) N-(4-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]phenyl)metha nesulphonamide;
• or
• the resolved enantiomers thereof, and the salts, solvates, hydrate and N-oxides thereof.

A pharmaceutical composition comprising a compound of formula (1) ##STR22## wherein Y is halogen or --OR.sup.1, where R.sup.1 is substituted or unsubstituted C.sub.1-6 alkyl, said R.sup.1 substituent being halogen;

• X is --O--, --S-- or --N(R.sup.8)--, where R.sup.8 is hydrogen or C.sub.1-6 alkyl;
• R.sup.2 is substituted or unsubstituted C.sub.3-8 cycloalkyl or substituted or unsubstituted C.sub.3-8 cycloalkenyl, said R.sup.2 substituents being halogen, C.sub.1-6 alkyl, hydroxyl or C.sub.1-6 alkoxy;
• R.sup.3 is hydrogen, halogen or --OR.sup.9, where R.sup.9 is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.1-3 alkoxyC.sub.1-3 alkyl, substituted or unsubstituted C.sub.1-6 alkanoyl, HC(.dbd.O)--, --CONR.sup.11 R.sup.12 or --CSNR.sup.11 R.sup.12 where each of R.sup.11 and R.sup.12 is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl;
• said R.sup.3 substituents being halogen, C.sub.1-6 alkyl, hydroxyl or C.sub.1-6 alkoxy;
• each of R.sup.4 and R.sup.5 is independently --(CH.sub.2).sub.n Ar, where n is an integer of 0 to 3, and Ar is monocyclic or bicyclic, substituted or unsubstituted C.sub.6-12 aryl, or monocyclic or bicyclic, substituted or unsubstituted heteroaryl selected from the group consisting of pyrrolyl, furyl, thienyl, imidazolyl, N-methylimidazolyl, N-ethylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryl, isobenzofuryl, benzothienyl, isobenzothienyl, indolyl, isoindolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolinyl, isoquinolinyl, tetrazolyl, 5,6,7,8-tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl, said R.sup.4 and R.sup.5 substituents being R.sup.13 or --Alk.sup.1 (R.sup.13).sub.m ;
• each of R.sup.6 and R.sup.7 is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl, said R.sup.6 and R.sup.7 substituents being halogen, hydroxyl or C.sub.1-6 alkoxy;
• R.sup.13 is halogen, --NH.sub.2, substituted --NH.sub.2, nitro, cyano, --OH, --OAlk.sup.1 (R.sup.13a).sub.m, cycloalkoxy, HC(.dbd.O)--, --CO.sub.2 H, esterified --CO.sub.2 H, --SH, --SAlk.sup.1 (R.sup.13a).sub.m, --C(.dbd.O)Alk.sup.1, --SO.sub.3 H, --SO.sub.2 Alk.sup.1, --SO.sub.2 NH.sub.2, --SO.sub.2 NHAlk.sup.1, --SO.sub.2 N(Alk.sup.1).sub.2, --CONH.sub.2, --CONHAlk.sup.1, --CON(Alk.sup.1).sub.2, --NHSO.sub.2 H, --NHSO.sub.2 Alk.sup.1, --N(SO.sub.2 Alk.sup.1).sub.2, --NHSO.sub.2 NH.sub.2, --NHSO.sub.2 NHAlk.sup.1, --NHSO.sub.2 N(Alk.sup.1).sub.2, --NHC(.dbd.O)Alk.sup.1 or --NHC(.dbd.O)OAlk.sup.1 ;
• R.sup.13a is halogen, --NH.sub.2, nitro, cyano, --OH, cycloalkoxy, HC(.dbd.O)--, --CO.sub.2 H, esterified --CO.sub.2 H, --SH, --C(.dbd.O)Alk.sup.1, --SO.sub.3 H, --SO.sub.2 Alk.sup.1, --SO.sub.2 NH.sub.2, --SO.sub.2 NHAlk.sup.1, --SO.sub.2 N(Alk.sup.1).sub.2, --CONH.sub.2, --CONHAlk.sup.1, --CON(Alk.sup.1).sub.2, --NHSO.sub.2 H, --NHSO.sub.2 Alk.sup.1, --N(SO.sub.2 Alk.sup.1).sub.2, --NHSO.sub.2 NH.sub.2, --NHSO.sub.2 NHAlk.sup.1, --NHSO.sub.2 N(Alk.sup.1).sub.2, --NHC(.dbd.O)Alk.sup.1 or --NHC(.dbd.O)OAlk.sup.1 ;
• Alk.sup.1 is straight or branched C.sub.1-6 alkylene, C.sub.2-6 alkenylene or C.sub.2-6 alkynylene, optionally interrupted with up to three --O--, --S--, --N(R.sup.8)-- or --S(O).sub.p -- groups or, when Alk.sup.1 is a substituent, Alk.sup.1 is straight or branched C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl, optionally interrupted with up to three --O--, --S--, --N(R.sup.8)-- or --S(O).sub.p -- groups;
• m is an integer of 0 to 3;
• and
• p is 1 or 2;
• or the salt, solvate, hydrate or N-oxide thereof;
• together with one or more pharmaceutically acceptable carders, excipients or diluents.

A method of preventing or treating an inflammatory disease in a patient comprising administering to said patient, in combination with a pharmaceutically acceptable carrier, a selective inhibitor of a phosphodiesterase (PDE) IV isoenzyme in an amount sufficient to elevate intracellular levels of adenosine 3',5'-cyclic monophosphate (cAMP), said inhibitor being selected from a compound of the formula:

• ##STR23## wherein Y is halogen or --OR.sup.1, where R.sup.1 is substituted or unsubstituted C.sub.1-6 alkyl, said R.sup.1 substituent being halogen;
• X is --O--, --S-- or --N(R.sup.8)--, where R.sup.8 is hydrogen or C.sub.1-6 alkyl;
• R.sup.2 is substituted or unsubstituted C.sub.3-8 cycloalkyl or substituted or unsubstituted C.sub.3-8 cycloalkenyl, said R.sup.2 substituents being halogen, C.sub.1-6 alkyl, hydroxyl or C.sub.1-6 alkoxy;
• R.sup.3 is hydrogen, halogen or --OR.sup.9, where R.sup.9 is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.1-3 alkoxyC.sub.1-3 alkyl, substituted or unsubstituted C.sub.1-6 alkanoyl, HC(.dbd.O)--, --CONR.sup.11 R.sup.12 or --CSNR.sup.11 R.sup.12 ;
• where each of R.sup.11 and R.sup.12 is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl;
• said R.sup.3 substituents being halogen, C.sub.1-6 alkyl, hydroxyl or C.sub.1-6 alkoxy;
• each of R.sup.4 and R.sup.5 is independently --(CH.sub.2).sub.n Ar, where n is an integer of 0 to 3, and Ar is monocyclic or bicyclic, substituted or unsubstituted C.sub.6-12 aryl, or monocyclic or bicyclic, substituted or unsubstituted heteroaryl selected from the group consisting of pyrrolyl, furyl, thienyl, imidazolyl, N-methylimidazolyl, N-ethylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryl, isobenzofuryl, benzothienyl, isobenzothienyl, indolyl, isoindolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolinyl, isoquinolinyl, tetrazolyl, 5,6,7,8-tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl, said R.sup.4 and R.sup.5 substituents being R.sup.13 or --Alk.sup.1 (R.sup.13).sub.m ;
• each of R.sup.6 and R.sup.7 is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl, said R.sup.6 and R.sup.7 substituents being halogen, hydroxyl or C.sub.1-6 alkoxy;
• R.sup.13 is halogen, --NH.sub.2, substituted --NH.sub.2, nitro, cyano, --OH, --OAlk.sup.1 (R.sup.13a).sub.m, cycloalkoxy, HC(.dbd.O)--, --CO.sub.2 H, esterified --CO.sub.2 H, --SH, --SAlk.sup.1 (R.sup.13a).sub.m, --C(.dbd.O)Alk.sup.1, --SO.sub.3 H, --SO.sub.2 Alk.sup.1, --SO.sub.2 NH .sub.2, --SO.sub.2 NHAlk.sup.1, --SO.sub.2 N(Alk.sup.1).sub.2, --CONH.sub.2, --CONHAlk.sup.1, --CON(Alk.sup.1).sub.2, --NHSO.sub.2 H, --NHSO.sub.2 Alk.sup.1, --N(SO.sub.2 Alk.sup.1).sub.2, --NHSO.sub.2 NH.sub.2, --NHSO.sub.2 NHAlk.sup.1, --NHSO.sub.2 N(Alk.sup.1).sub.2, --NHC(.dbd.O)Alk.sup.1 or --NHC(--O)OAlk.sup.1 ;
• R.sup.13a is halogen, --NH.sub.2, nitro, cyano, --OH, cycloalkoxy, HC(.dbd.O)--, --CO.sub.2 H, esterified --CO.sub.2 H, --SH, --C(.dbd.O)Alk.sup.1, --SO.sub.3 H, --SO.sub.2 Alk.sup.1, --SO.sub.2 NH.sub.2, --SO.sub.2 NHAlk.sup.1, --SO.sub.2 N(Alk.sup.1).sub.2, --CONH.sub.2, --CONHAlk.sup.1, --CON(Alk.sup.1).sub.2, --NHSO.sub.2 H, --NHSO.sub.2 Alk.sup.1, --N(SO.sub.2 Alk.sup.1).sub.2, --NHSO.sub.2 NH.sub.2, --NHSO.sub.2 NHAlk.sup.1, --NHSO.sub.2 N(Alk.sup.1).sub.2, --NHC(.dbd.O)Alk.sup.1 or --NHC(.dbd.O)OAlk.sup.1 ;
• Alk.sup.1 is straight or branched C.sub.1-6 alkylene, C.sub.2-6 alkenylene or C.sub.2-6 alkynylene, optionally interrupted with up to three --O--, --S--, --N(R.sup.8)-- or --S(O).sub.p -- groups or, when Alk.sup.1 is a substituent, Alk.sup.1 is straight or branched C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl, optionally interrupted with up to three --O--, --S--, --N(R.sup.8)-- or --S(O).sub.p -- groups;
• m is an integer of 0 to 3;
• and
• p is 1 or 2;
• or the salt, solvate, hydrate or N-oxide thereof;
• together with one or more pharmaceutically acceptable carriers, excipients or diluents.